Pharmacology of Movement Flashcards
What are the genes associated with Parkinson’s?
- SNCA - involves alpha-synuclein protein, Aggregates into clumps (Lewy bodies)
- LRRK2 - most common genetic contributor to Parkinson’s, kinase, specialised protein type which modifies other proteins
What are the main features of PD?
- resting tremor
- bradykinesia
- rigidity
- frozen facial expression
- flexed posture
- altered gai/postural changes
- difficulty initiating and stopping movement
What are some non-motor features of PD?
Olfactory depression Depression Psychotic symptoms Cognitive dysfunction Dementia Sleep disturbance Autonomic dysfunction
How are dopaminergic neurons degenerated?
- MPTP (methyl-phenyl-tetrahydropyridine) is transformed into metabolite MPP+ which is neurotoxic
- MPP+ causes dysfunction of complex I of mitochondrial respiratory chain = oxidative stress
- dopamine easily oxidised -> free radicals produced
- monoamine oxidase involved
How is dopamine synthesised?
L-Tyrosine -> L-Dopa (via tyrosine hydroxylase)
L-Dopa -> Dopamine (via L-aromatic amino acid decarboxylase)
How is dopamine metabolised?
Dopamine -> DOPAC (MAO and aldehyde dehydrogenase)
DOPAC -> Homovanillic acid (via COMT)
What are the treatments for Parkinson’s in regards to dopamine?
L- dopa direct administration
L-dopa decarboxylase inhibitor
MOA and COMT inhibitors
What are the 3 pathways in which projection neurons can release dopamine?
Mesocortical
Nigostriatal
Mesolimbic
What are the dopamine receptors?
GPCRs
- D1 like (D1 and D5)
- D2 like (D2, D3, D4)
How can L-Dopa treat PD?
Directly compensates for decreased dopamine levels
What are some precursors of L-Dopa?
Carbidopa Benserazide (levodopa)
What are some adverse effects of L-Dopa?
Nausea/vomiting Postural hypotension Psychosis Impulse control disorders Motor complications - on and off effect, dyskinesia
What are some dopamine agonists?
Rotigotine: transdermal patch
Apomorphine: infusion
What are MAOb inhibitors?
Stop dopamine breaking down due to oxidatio
What are some examples of MAOb inhibitors?
Rasagiline
Selegiline
Why are anticholinergic compounds used?
Loss of dopamine = increased activity of cholinergic cells = hyperactivity
What are some examples of anticholinergics?
Orphenadrine
Procyclidine
What is the role of amantadine?
Inhibits reuptake of dopamine
Increases release of dopamine
What are some examples of COMT inhibitors?
Entacapone
Tolcapone
What are some other treatment methods to PD?
- human embryonic mesencephalic graft (releases dopamine)
- surgical approaches (stimulates certain structures/lesions such as the subthalamic nucleus/pallidotomy causes slight damage to globus pallidus)
What is the cause of Huntington’s?
Changes in gene coding protein huntingtin on chromosome 4
- abnormal glutamine repeats in sequence
- gain of function = mutated protein aggregates in cells
- striatal neuron degeneration and cortical atrophy
How does neurodegeneration occur?
Loss of medium size spiny neurons Intranucleus inclusions of huntingtin Excitoxicity Loss of neurotrophic factors Dysregulation of transcription Increased oxidative stress Abnormalities in axonal transport
What are the symptoms of Huntington’s?
Choreic movements Gait abnormalities Lack of coordination Cognitive impairment Psychiatric disturbances Sleep disturbance Weight loss
What are the 3 methods of treatment for Huntington’s?
- tetrabenazine: reduces chorea, reversible depletion of monoamines like dopamine
- haloperidol/olanzapine: antipsychotic, higher affinity for serotonin transporters than dopamine
- imipramine/amitriptyline: TCA depressant, stronger effect on serotonin transporters, nearly no effect on dopamine transporters
